Tuberculosis, one of the oldest-known diseases, is caused by the infection of Mycobacterium tuberculosis, and even to this day is still seriously harmful to human health. According to the statistics of WHO, about ⅓ of people have been infected by Mycobacterium tuberculosis across the world, tuberculosis is an infectious disease which caused the largest number of deaths.
The current treatment of tuberculosis mainly uses the drug combination method of several first-line drugs such as isoniazide, rifampicin, ethambutol and pyrazinamide. This therapeutic method has the following disadvantages: long treatment cycle, often requires more than half a year; serious adverse reaction, eg., the drug combination of rifampicin and isoniazide is possible to cause serious liver disease, ethambutol can cause nerve injury; poor effect for drug resistance Mycobacterium tuberculosi, especially for multi-drug resistance Mycobacterium tuberculosi(MDR-TB), even ineffective.
WO9701562 disclosed a type of nitroimidazoles compound, particularly PA-824, which has a novel mechanism of action and can be used to treat tuberculosis. However, due to its low water-solubility and low bioavailability, PA-824 needs to be formulated into complex tablet formulation when administrated orally, and needs to further enhance its antitubercular activity [Bioorg. Med. Chem. Lett, 2008, 18(7), 2256-2262.].
Otsuka Pharmaceutical Co., Ltd also synthesized many nitroimidazoles compounds, particularly OPC-67683 [Journal of Medicinal Chemistry 2006, 49(26), 7854-7860], which acts similarly to PA-824 and is used to treat tuberculosis, but has the same problems as PA-824, especially water-solubility that limits its pharmacokinetics characters, and can be further improved.
In view of the above, there exists an urgent need to develop a novel antituberculosis drug in the art. This novel drug should have the following characteristics: effective for drug-resistance bacteria, especially multi-drug resistance bacteria; can be used combined with currently used first-line antituberculosis drugs; has ideal metabolic property, can be administrated orally.